This invention is directed to substituted (aminoiminomethyl or aminomethyl)benzoheteroaryl compounds that inhibit Factor Xa, pharmaceutical compositions comprising these compounds and use of the compounds for inhibiting Factor Xa or otherwise treating a physiological condition in a patient that may be ameliorated by administering these compounds to the patient.
Factor Xa is the penultimate enzyme in the coagulation cascade. Both free Factor Xa and Factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phosphiolipid) are inhibited by compounds of formula I. Factor Xa inhibition is obtained by direct complex formation between the inhibitor and the enzyme and is therefore independent of the plasma co-factor antithrombin III. Effective Factor Xa inhibition is achieved by administering the compounds either by oral administration, continuous intravenous infusion, bolus intravenous administration or any other parenteral route such that it achieves the desired effect of preventing the Factor Xa induced formation of thrombin from prothrombin.
Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting of the coronary (CABG) or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus fonnation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary throinboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors resulting in the formation of life-threateniling clots throughout the microvasculature of several organ systems.
Accumulated experimental evidence has also reflected that prothrombin activation is only one of the biological activities of Factor Xa. EPR-1 (effector cell protease receptor-1, recognizing Factor Xa), is believed to mediate several of the vascular wall interactions by Factor Xa. It has been shown to be expressed on human umbilical vein endothelial cells, rat smooth muscle cells and platelets(CR McKenzie, et al., Arterioscler Thromb Vasc Biol 16 1285-91 (1996); also F Bono, et al., J Cell Physiol 172 36-43 (1997), AC Nicholson, et al., J Biol Chem 271 28407-13 (1996), J. M. Herbert, et al., J Clin Invest 101 993-1000 (1998)). This protease-receptor interaction could mediate not only prothrombinase-catalyzed thrombin generation, but also diverse cellular functions such as cell proliferation, release of PDGF and DNA syntheses. The mitogenic effect of Factor Xa has been reported to be dependent on Factor Xa enzymatic activity (F Bono, et al., J Cell Physiol 172 36-43 (1997), J. M. Herbert, et al., J Clin Invest 101 993-1000 (1998)). TAP for example inhibited the mitogenesis of human and rat cultured vascular smooth muscle cells (F Bono, et al., J Cell Physiol 172 36-43 (1997)). In a study of the rabbit carotid artery air-drying injury model, increased EPR-1 expression was detected after vascular injury. Animals treated with the specific Factor Xa inhibitor, DX-9065a, exhibited less neointimal proliferation. The important regulatory role of Factor Xa in the coagulation process coupled with its mitogenic effects points to Factor Xa""s involvement in the formation of thrombin at the luminal surface of the vessel wall and contribution to the atherothrombotic process and abnormal proliferation of vascular cells resulting in restenosis or angiogenesis.
In view of the physiological conditions discussed above related to Factor Xa, inhibitors of Factor Xa would be useful in treating those conditions and others that would be ameliorated by a Factor Xa inhibitor.
H. E. Lape, et al, Arch. lnt. Pharmacodyn., 171(2) 394414 (1968) disclose the following optionally alkyl substituted indole-(1 or 3)-acetamidoxime compounds wherein X is CH or N, and n is 0-2
A wide range of antihypertensive activity is noted regarding the compounds. There is no disclosure or suggestion that the acetamidoxime compounds exhibit Factor Xa activity.
European Patent Application Publication No. 568,289 discloses the following 2-carboxamidine benzothiophene compounds wherein at least one of R2, R3, R4 and R5 is an organic group 
which includes 5 or more carbons, an organic group which contains a sulfur atom or hydroxy, an unsaturated organic group or a cyclic organic group. The compounds are noted to be urokinase inhibitors. European Patent Application Publication No. 568,289 does not disclose or suggest 3-carboxamidine benzothiophene compounds or that the 2-carboxamidine benzothiophene compounds exhibit Factor Xa activity.
This invention is directed to a compound of formula I: 
wherein
X is O, S or NR1;
R is hydrogen, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl or fused heterocyclylheteroaryl, provided that when L2 is a chemical bond, then Q is attached to R through a carbon atom thereof and, when R is hydrogen then L2 is not a chemical bond;
R1 is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl, heteroaroyl, alkoxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl;
R2 and R3 are hydrogen, or taken together are xe2x95x90NR4;
R4 is hydrogen, R5O2Cxe2x80x94, R5Oxe2x80x94, HOxe2x80x94, cyano, R5COxe2x80x94, HCOxe2x80x94, lower alkyl, nitro, or R6R7Nxe2x80x94;
R5 is alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl;
R6 and R7 are independently hydrogen or alkyl;
L1 is alkylene, alkenylene or alkynylene;
L2 is a chemical bond, alkylene, alkenylene or alkynylene;
Q is xe2x80x94NR8xe2x80x2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94NR8xe2x80x2C(X1)xe2x80x94, xe2x80x94C(X1)NR8xe2x80x2xe2x80x94, xe2x80x94NR8C(X1)Oxe2x80x94, xe2x80x94OC(X1)NR8xe2x80x94, xe2x80x94NR8C(X1)NR8xe2x80x94, xe2x80x94NR8C(X1)NR8xe2x80x94, xe2x80x94S(O)nxe2x80x94, xe2x80x94NR8SO2xe2x80x94 or xe2x80x94SO2NR8xe2x80x94, provided that a nitrogen atom or oxygen atom of Q is not directly bonded to a carbon atom of L1 or L2 having a double bond or triple bond, or Qxe2x80x94L2xe2x80x94R is cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, fused arylcycloalkyl, fused heteroarylcycloalkyl, fused arylcycloalkenyl, fused heteroarylcycloalkenyl, fused arylheterocyclyl, fused heteroarylheterocyclyl, fused arylheterocyclenyl, fused heteroarylheterocyclenyl, aryl, fused cycloalkenylaryl, fused cycloalkylaryl, fused heterocyclylaryl, fused heterocyclenylaryl, heteroaryl, fused cycloalkylheteroaryl, fused cycloalkenylheteroaryl, fused heterocyclenylheteroaryl or fused heterocyclylheteroaryl, provided that a nitrogen atom or oxygen atom of Q is not directly bonded to a carbon atom of L1 having a double bond or triple bond;
X1 is O or S;
R8xe2x80x2 is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl, heteroaroyl or alkoxycarbonyl;
R8 is hydrogen, alkyl, aralkyl, heteroaralkyl, acyl, aroyl or heteroaroyl; and
n is 0, 1 or 2, or
an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.